Phosphatide emulsifying agent and process of preparing same



v U 2,945,369,?1 I i v imosrnArmn EMULSIFYING AGENT AND i rnocnss OFPREPARING SAME r Curtis'E; Meyer, Charleston Township, Kalamazoo County, James "A. Fanchr, Kalamazoo, and Paul E. Schurr,Portage Township, Kalamazoo County, Mich,

' assignors-to The Upjohn Company, Kalamazoo Mich.,

.a corporation of Michigan i s No Drawing Filed Apr. 30, 1956, Ser. No. 581,269

i 6 Claims. crew-403 undesirable. reactions following intravenous administration to humans or animals. However, even that preparation causes some clinical reactions, amounting to approximately thirty percent of the patients treated. These reactions'consist of chills, fever, backache, chest pain,.

nausea, vomiting, dyspnea, apnea,. blood pressure eifects and the like. The reactions are all the more troublesome because many of them are not observed in the,

usual laboratory animals. It has now been discovered that a particular soyaphosphatide fraction will'produce a-suitable intravenous fat emulsion which significantly reduces the number of the previously indicatediundesin able reactions. i,

. It is therefore an object of the present invention to provide a therapeutic fat product which' is especially well-suited for intravenous use in human beings or animals. Another object of the presentinvention is to provide atherapeutic fat product whichis physically. and chemically stable and which has significantly fewer undesirable reactions than previously existing products when administered intravenously to human beings. A further object is the provision vofsuch a product which has a much lower incidencei ofclinical reactions, such as nit-Cd k 31 cm 2,945,869 Patented ul 19,19

.. plirposaralthough other co-ernulsifiers may-befusedsati s factorily. The condensation product is 'characterizedfas a polyalkylene glycol in which the alkylene units con; sist of ethylene and propylene units, said propylene units being in non-terminal f positions and connec ed to leach 1;.

otherina chain. v This invention also provides (1) a novel soya phos; .phatide'fraction which is essentially unreactive in the clinic andwhich can be-used as an emulsifier amine therapeuticfat product and (2) a novel process'for the preparation of the said soya phosphatide fraction. The metabolizable, non-toxic, fixed oils suitable for the therapeuticrfat product includenaturally-occurring vegetableand'animal oils, as well as synthetic oils. Those found to be most suitableare cottonseed oil, olive oil, peanut oil, coconut oil, sesame oil, corn oil and the like. An example of a suitable synthetic oil is that disclosed, in US. PatentNo; 2,728,706., Mixtures ofthe foregoing oils can alsobe used; Cottonseed oiland olive oil are preferred; H r I 1 The physical stability of the emulsion of these, oils is important. Particles of these oilsos hould be less-than.

about 2.5microns in diameter and preponderantly below about 0.5 micron in diameter. These particle sizes. should bestableunder various test conditions considered a valid indicators of physical stability, for p li"arrnaceutical.

fat emulsions. L Isotonic agents are desirablefor'intravenous fat'prod -j ucts since they impart properitonicity to theemulsion; Metabolizable sugars and polyhydroxyalcoholsare well-. suited for this purpose. Suitablesuga'rs arethe mono-I saccharides, such. as glucose ,(dextrose) and fructose;

Suitable polyl ydroxy alcohols include sorbitoli I The ethylene oxide-polypropylene glycol condensation. product used as co-emulsifier in thefat product is dc fined in U .S P atent No. 2,674,619 andco-pending an: plica'tion Serial No, 456,637 filed'septembe'rilc 1954. They are represented by the. following formula:

otczuima' nsm m nu wherein n, b and c are positive integers which can be varicdover awiderange. Within thelimit ations inherent chills, backache, chest pain, nausea, vomiting, dysphea, j

apnea, blood pressure effects, and the like,vwhen used intravenously in human, beings; Still another object ,is the provision of a. new, essentially unreactive soya phos phatide fraction which-c an be'used as an emulsifier for.

i A further object is the" an intravenous fat product. 7 V r provision of a process for thepreparation of such a soya phosphatide fraction. Other objects will be apparent to one skilled in the art to which this invention pertains f 65 The foregoing and additional objects have been accomplished by the provision of a therapeutic fatproductj which is especially suitable for intravenous use in human beings and which comprises a metabolizable, non-toxic,- .fixed oil emulsified in an, aqueous vehicle by a stable soya phosphatide fraction 1) which does not depress blood pressure when injected into anesthetized cats, and

(2) which can be prepared by adsorbingthe undersirable reactive materials found in the monatomic, lower molecular weight aliphatic alcohol-soluble soya phosphatides on an adsorbent selected from the group consisting of aluminum oxide, magnesium. oxide and activated" carbon. It is preferred that a" co-emulsifier be used with the soya'phosphatide fraction of-the present composition: The ethylene oxide-polypropylene 'glycolf conden sationxproduct more particularly described inco-pending application; Serial N0. $56,637,. is most suitable ior the oxidein themolecule. The base i sjthepolypropylen in the preferredcomposition 'o'ffthe present invention, "it

is desirable to use a-formulahavingfla base molecular.

weightbetween about 1500 an bout 18 00, with b tween about eightly" and about ninety percent 1 ethylene glycol u'nit. Such a formula canalso be designated reference to'- the structural formula as one 'in which" b equals between 'about 2-5 and about 32 and zi-l-c equals between-about 136 andaboutf368 Zen-example "of'a'."

. product coming'within the. a uveindi'cateai preferredzi.

specifications-is .Pl'uronicflF68manufactured by th Wyandotte Chemical Corporation; t

n An antioxidant-can be added to prevent'bxidation of: the oils during'processing and rancidity during storage}. Metabolizable antioxidants of'the phenolic type, such' as" tertiary, butyl anisoles andthelike,,"are'suitable.. It preferred to use a combination of tertiary butyl-4-hydroxy5, I

anisole, propylgallate and'citricacid. f i, o The concentrations of various ingredients which can be f utilizedin' the presentcornposition can be varied over a Widerang'eI However, the desirable overall characten'sr lv tics tend to 'limit somewhat the permissible fvariaticns of the concentration of the particular ingredients. f One such characteristic is the caloricvalue of the fat and sugar ginl any particular combination. Another characteristic which tends to limit the amount of the ingredients the vis--.,Q

cosity of the suspension. It is not desirable that the weight. of the oil exceeds about fifty percent wt./vol., otherwise the'pi oduct'tendsto betoo viscous for injection, Pra

.ylthe caloric" standpoint, -the lowerilimit for'an intravenous The concentration of sugar in thecomposition of the present invention should be between about three percent and ten percent wt./vol. of thewater, preferably about five percent.

" Although the therapeutic fatproduct of the present invention is primarily designed for intravenous use, the

composition can also be used orally. However, a successful oral product would not require that the phosphatides be processed to the same extent as for an intravenous product. The concentrations indicated above would, of

course, be somewhatedifierent for an oralproduct than for an intravenous product.

'Once the concentrations of the oils and sugars have been fixed within the ranges specified above, the concentration of the soya phosphatide fraction for intravenous use can be varied between about 0.5 to about three percent wt./vol. (1.2 percent preferred). The concentj ration of the preferred ethylene oxide-polypropylene glye01 condensation product can be varied from about 0.2 to about 0.5 percent wt./vol. (0.3 percent preferred) for the intravenous product. Thus, the amounts of the emulsifiers utilized in the, composition of the'present invention depends'upon the amount of oil chosen.

In carrying out the process of preparing the soya phosphatide fraction of the present invention, commercially available soya phosphatides, such as Lecithin RG (Glidden), or the alcohol-soluble fraction of soya phosphatides (e.g., Lecithin RAS, Glidden), can be used as starting material. It is desirable that each of these products be extracted with a monatomic, .lower molecular weight aliphatic alcohol, e.g., methanol, ethanol, propanol, isopropanol, or mixtures thereof. Ethanol is preferred, partly because of higheryield and partly because it is ,less toxic if incompletely removed from the product. It is preferred that this extraction be canied out at about room temperature. Absolute ethanol need not be used. In fact alcohol U.S.P. (not less than'94l9 percent by volume of C H OH) is preferred. If thirty percent or more water is used, however, the desirable phosphatide fraction will also partially precipitate out. Thus, ethanol in a concentration; of'85 to 100 percent is operative; I t

Thisalcohol soluble fraction is notentirely satisfactory since it still contains reactive substances which, when madeup into a fat emulsion, forintravenous use, causes. thefundesirable clinicalreactions noted above. It is necessary, therefore, that the alcohol-solublev fraction be contactedwithv anadsorbent selected from thegroup consisting of aluminum oxide, magnesium, oxide and activated carbon. Acid washedcarbong should. be. avoided. The" substances remain adsorbed on the adsorbent, and the soya phosphatide fraction'which remains dissolvedv the alcohol will not only provide a suitable emulsifier for the intravenous fat, productof the present invention,

but will also eliminate or significantly reduce such un desirable. effects as chills, backache, chest. pain, nausea, vomiting, dyspnea, apnea, blood pressure effectsand the 1il 'e, when made up into a fat emulsion.

Inthe preferred embodiment of the process of purifi-, cation, the ethanol-s oluhle-portion of soya phosphatide in about ten vol./wt. of ethanol is stirred with'about two part by weight of aluminum oxide for aboutthirty minutes atroqrn temperature. The adsorption time can be reduced to as little as ten minutes, and the adsorption will be satisfactory: When the aluminumoxideis re-' dircedfin quantity to as low as 1.5 parts :by weight, the

pr u tproduced is unsatisfactory. After the aluminum ox id e rs filtered out, the alcohol is removed under re,-

, dlteedpressure, and the. material is.taken up in an approprtate an quntlpf vegetable, oilfo'r the, preparation of an As of table. screen to determinefthe clinical reactiveness oya phosphatidefraction is the, test for blood de;

pressor effects in cats. If the blood depressor effect is not observed in an anesthetized cat, the material tested will not possess such undesirable reactions when administered to humans. The cat test referred to herein is substantially that described by. .Geyer et al., J. Lab. Clin. Med.

34, 688 (1949). Geye r et al. reported that the phosphatide fraction prepared by the :use of solvents was nonreactive in cats when freshly prepared. However,

emulsions. prepared with this material became reactive Within four days. The soya phosphatide fraction useful in the composition of the present invention does not become reactive when used in an emulsion and stored for a V considerable period of time.

7 'wherein the Rs represent fatty acids which'have been In carrying out the cat test a cat is, anesthetized with sodium salt of 5-ethy1-5-(l-methylbutyl)-barbituric acid. The jugular vein and carotid artery are canulated. The carotid artery is connected to a mercury manometer equipped to record blood pressure. An intravenous injection of the material to be tested, e.g., a soya phosphatide fraction, is added via the jugular canula, and the blood pressure is recorded, noting the rise or fall. If a fall in pressure isto occur at all, it will occur almost immediate 13 after injection.

The chemical composition of the soya phosphatide fraction of the present invention cannot be characterized exactly. This is generally true of any mixture of phosphatides derived from natural sources. Thecomplexity of the problem is shown by many papers appearing in the literature, e.g., Scholfield et aL, J. Am. Oil. Chem. Soc., 25, 368 (1948). Howevenfrom the standpoint of reproducibility and practical utilization, the soya phosphatide fraction can be characterized as a stable fraction of soya phosphatides (1) which does not depress blood pressure when injected into anesthetized cats, (2) which can be prepared by adsorbing the undesirable reactive materials found in the monatomic, lower molecular weight aliphatic alcoholsoluble soya phosphatides on an adsorbent selected fromthe group consisting of aluminum oxide, magnesium oxide and activated carbon, and (3) which is a satisfactory emulsifier for the oil used in a therapeutic fat product.

In addition, the soya phosphatide fraction can be characterized' chemically. sufficiently todifferentiate it from the whole soya: phosphatides and other fractions thereof.

found by Hilditch and Pedelty (Wittcotf, The, Phosphatides, ReiuholdPublishing Corp., 1951, p. 223-) to be present in soybean phosphatides as:

Percent Palmitic 11.7

Stearic 4.0 Arachidic 1.4 Hexadecenoic 8'.6

Oleic 5.5' Linoleic 63.3 C unsat. 5.5

1 Includes some. linolenic.

In lecithin R :choline.

In cephalins R=ethanolamlne, sertne or-inosito1,- although in the case of inositol this structure is-an overslmpllficatlon;

Total nitrogen is therefore a measureof all the-phosphatides (if thatis all the nitrogen-containing materia that is present) except phosphatidylinositol. I

t'ion'value and iodine value of the phosphatides and the neutral equivalent and iodine value of the tatty'acids is a measure'and, description of'theaverage of the fatty acids present. J

Amongthe most significant figures are those of choline, serine, and ethanolamine, which can be translated into the parent compounds." It is also evident that for a pure compound the molecular ratio of one of these constituents, e.g., choline in the case of lecithin, to P is unity.

The value for inositol is also important, as the present state of knowledge indicates that it is an integral part of several phosphatides whose structures have not been definitely determined. v

In the soya phosphatide fraction of the present invention, the proportion of lecithin has been increased while the proportion of cephalin components, especially the inositol, have been reduced. This is suggestive that inositol might be the undesirable active ingredient, but at the present time this is merelya good guess. i at K In the analysis, the present soya phosphatide fraction is a material having approximately this composition which does not. causea fall inthe blood pressure'of the anesthetized cat. I V

The following examples are illustrativeof. thecomposition of the present invention but are not'to be construed aslimiting. I

EXAMPLE 1 300 grams or a granular soyaphosphatide '(Glidden.

Lecithin RG) which has been shown to have high de-- pressor activity in cats were extracted three times with (SOD-milliliter portions of absolute ethanol in aWaring,

Blendor forl-Z minutes at room temperature. The extracts were clarified by gravityfiltration and concentrated under reduced pressure to 250 milliliters. A solids determination. indicated 95.7 grams of material were extracted.

73.5 milliliters containing 28 grams were put on a column of two pounds of aluminum oxide and developed with 95 i percentaqueous ethanol. Fractions were taken.

. m1. gm.

N0. 1 595 1. N0. 2 1, 016 6. N0. 3 616 1. N0. 4 a 2, 317 2.

Fraction No. 2 was concentrated under reduced pressure for removal of alcohol. The residue was taken up in sufficient water to give a 1.2 percent solution; of the solu' tion was used to make up a five percent dextrose preparation, /2 of which was autoclaved. 'When' these three solutions were injected into anesthetized cats through a jugular canula, they were found to be free pressor activity.

EXAMPLE 2 Skellysolve B. The solution was poured into ninety milliliters of acetone, whereupon an oil separated. The

acetone-Skellysol-ve was decanted from the oil, which was then treated three times with acetone. The residue was freed of acetone in a vacuum desiccator. A 1.2 percent solutionof the material in a five precent aqueous glucose solution did not depress blood pressure in the cat when injected at a level of 0.5 to five milliliters per kilogram.

EXAMBLE '3 300 grams of an alcohol-soluble fraction, of soya phosphatide '(Glidden Lecithin RAS) were dissolved in 1500 milliliters of aqueous ethanol 95 percent on, a steam bath. The solution was allowed to come to room temperature.

of blood pressure de- 1 6 A gummy plastic residue which separated was removed by centrifugation. 1380 milliliters of solution were re covered. It was divided into' two parts; 700 milliliters were placed in the refrigerator for six days.

decanted and to 100 milliliters of the supernatant containing 9.3 grams of solids were added 18.6 grams of -aluminum oxide, Merck chromatographic. The mixture was shaken for thirty minutes. After removal of the aluminum oxide and alcohol, a 1.2 percent solution of the residual material was made in a five percent aqueous solu: tion of dextrose. Five milliliters per kilogram injected into a cat gaveno unrefrigerated portion of the original solution, 680 milli liters, was allowed to stand at room temperature one day. Unidentified amorphous material separated and was filtered off. The solution, containing 82.6 grams of solids, was stirred thirty minutes with 165.2 grams of aluminum oxide. After removal of the aluminum oxide and alcohol, a 1.2 percent solution of a portion of the residue was made in a five percent aqueous solutionof glucose. Five tnflliliters per kilogram did not lowerblo'od pressure in. cats. s EXAMPLE 4 v1235 milliliters of an alcohol solution containing 61.2 grams of soya phosphatide were stirred with 30.6 grams of aluminum oxide, Merck. A sample of the solution containing 1.29 grams of phosphatide was removed (1).

To the remaining solution 29.95 grams more aluminum oxide were added and stirred for thirty minutes. A sample was removed (2).

To the main solution another 23.2 grams of aluminum oxide were added and the process repeated (sample 3). Finally, another 21.5 grams of aluminum oxide were added to the remaining'solution and stirred thirty minutes (sample 4). A 1.2 percent solution of each sample was made in five percent dextrose and injected into cats.

Six kilograms of alcohol-soluble phosphatide (Glidden Lecithin Grade RAS) were extracted by stirring with 'sixty liters of aqueous alcohol percent) forfifteen minutes. Thiswas allowed to settle, and the supernatant.

was siphoned ofi. Twelve kilograms of aluminum oxide (Harshaw catalytic grade) were added to the supernatant, and the mixture stirred forthirty'minutes. The mixture was allowed to settle, and the supernatant filtered through an alcohol-washed Seitz filter pad.- Sixty liters of solution containing 2830 grams of the soya phosphatide frac 1 tion were obtained. The alcohol from 55.5 liters of this solution was removed in a flash still, 72 pounds of cottonseed oil being added during the process.

Using this oil-phosphatide solution, the following quan: titles of materials were prepared into an'emulsion:

Water for injection U.S.P. suflicient to make200liters.

Forty liters of water were filtered into a large tank, and

the temperature was raised to ninety degrees centigrade The dextrose was added and followed by Pluronic-F68L This mixture was pumped into another'large tank The.

first tank was washed withfilte'red water, and the wash water was also pumped into the second tank. .The solu g;

A heavyliquid layer settled to the bottom. The supernatant was' blood pressure depressor effect. The

7 tion in the second tank was filtered back into the first tank. The filter-was also washed into the first tank, adjusting to approximately eighty'liters. "At seventy-degrees Centigrade the phosphatide-oil solution was added, and volume was brought up to 120 liters by adding filtered water. The resulting mixture was mixed thoroughly for five minutes by rapid stirring and then homogenized at 4000 pounds per square inch for twenty minutes at seventy degrees centigrade, recycling into the first tankQ Meanwhile, eighty liters of water were placed in the second tank. The water from the second tank was added to the emulsion at seventy degrees centigrade. With prcssure at 4000 pounds per square inch, the-mixture was.

homogenized with a Manton-Gaulin homogenizer into tank 2. The last cycle was repeated twice, and the resulting emulsion was filtered into 600 milliliter centrifuge bottles. The emulsion was autoclaved at fifteen pounds per square inch for twenty minutes and cooled as rapidly aspossible f A This emulsion did not cause a fall of blood pressure in anesthetized cats and was free of serious clinical reactions when injected intravenously into human beings;

ten liters of aqueous-ethanol (95 percent) and stirred twenty minutes. The solution was allowed to settle. A gummy, plastic residue which separated was discarded after decantation of the supernatant. 10,700 milliliters of supernatant were recovered. The alcohol was removed from part of this supernatant and the residue analyzed. The results of the analyses appear under the column headed RAS/Al in Table I. To 300 milliliters of the supernatant were added sixty grams of aluminum oxide, Merck chromatographic, and the mixture was shaken for thirty minutes. After removal of'the aluminum oxide and alcohol, the residue was analyzed and possessed the analytical values shown in Table I. To still another 300-milliliter portion of the supernatant was added 45 grams of activated carbon (Norit-SG) and the mixture was shaken for thirty minutes. The carbon was filtered off; and since the filtrate still possessed a trace of color, it was again shaken for thirty minutes with an additional fifteen grams of activated carbon. The carbon was removed by filtration leaving a colorless filtrate and the alcohol was removed in vacuo yielding 2.48 grams of material. This material was analyzed and possessed the analytical values shown in Table I.

. Table I ANALYSES N VARIOUS PHOSPHATIDES Glidden Giidden A1 0; Activated Egg 1 Hanahan Lecithin Lecithin RAS/Al 1 Treated Carbon Phos. Egg

RG 5 RAS 6 Treated Lecithin Tot. Nitrogen, Percent 1. 1. 23 1.38 1. 44 1. 45 4. 15 1. 79 Tot. Phosphorus, Percent 3. 45 2. 44 2.48 3.01 2.84 6. 31 3. 90 Choline, Percent 3. 00 6. 23 7. 16- 10. 10. 04 13. 15.30 Inositol, Percent 2. 41 0. 207 0.08 0.01 0.04 02 7 Ethanolamine, Percent 1.9 1.3 0.93 0.47 0.4 0.30 0 Serine, Percent 0. 41 0.10 0.11 0.045 0.4 0.20 0 Iodine value (of whole i ction). 76. 1 92. 2 82.0 85. 9 69. 4 11.2 88.0 20) 8.57 3.42 3. 28 2. 61 3.00 10. 72 N:P mol. ratio.. 0. 736 1. 112 1. 23 1. 026 1.128 1. 440 1 00 Reducing Sub. (of hydrolyzed material) 13. 7 6. 7 2.16 28. 3 Fatty acids, Percent 55. 8 67. 1 66.1 70. 7 47. 8 19. 3 70. 0 Iodine Value (of fatty acid).... 124. 7 115. 5 116. 7 118. 2 105. 8 91. 0

1 Treated with A1 0; and activated carbon.

in an anesthetized cat 3 As galactose.

Norit-SG, American Norit Company.

A commercial sol'ci soya phosphatide mixture containing essentially allot the'phosphatidesas they occur in the soybean and differing from the fluid preparations (the Lecithins of commerce) in a lower oil content- 1 approximately four percent.

A commercial source of the alcohol-soluble fraction of the mixed soya phosphatides, having a higher content of lecithin and less of the cephalin fraction than RG.

Upon extractlng RAS with 10 v./w. of alcohol percent, we find that only about seventy percent of the material is now soluble. This is reflected in the reduced quantities of phosphatidylinositol and ethanolamine found which are the main components of the cephalin fraction.

EXAMPLE 6 The following quantities of materials were made into an emulsion in a Cherry-Burrell homogenizer.

Cottonseed oil (Wesson. oil) grams 375 Soya phosphatide fraction do 24 Pluronic F68 -do 7.5 Dextrose do Deionized water rnls 2000 Prepared in the manner described in Example 5. I

Repeated injections of this emulsion'intov cats at five to ten milliliters/kilogram has shown no evidence ofdepressor activity, whereas 0.1 milliliter/kilogram of an emulsion made with the same phosphatide prior to treatment gave as much as mm. Hgfall in blood pressure.

When used intravenously in human beings, this emulsion is free of serious clinical reactions.

EXAMPLE7 a.

The procedures used for determining the various values shown in Table I were as follows: Total nitrogen, Micro- Kjeldahl; phosphorus, Fiske and SubbaRow, J. Biol. Chem., 66, 375 (1925); choline, D. Glick, J. Biol. Chem.,

156, 643 (1944); ethanolamine and serine, separated by procedure of C. Artom, J. Biol. Chem., 157, 585 (1945), with determination by an adaptation of S. Moore and W. H. Stein, J. Biol. Chem. 211, 907 (1954); inositol, adaptation of the pyridoxine method of Atkin et al. (Anal. Ed.), Ind. Eng. Chem., 15, 141 (1943), using Sacch. carlsbergensis, ATCC 9080; fatty acids, two hour hydrolysis with 2 N sodium hydroxide in fiftypercent ethanol followed by acidification and extraction with petroleum ether; and iodine value, U.S.P.

it may be concluded from the table that the purified fraction of soya phosphatides obtained by the present process of a mixture of phosphatidylcholine (lecithin), phosphatidylethanolamine, and phosphatidylserine. Lecithin is the predominant constituent. Phosphatidylino sitol is essentially absent which may well be a significant characterizing feature. Circumstantial evidence indicates that phosphatidylinositol is the reactive or. most reactive agent which produces a fall in the blood pressure of .the

This material-still possessed the blood pressure depressor action Hanaha11etal.,1.13iol.Chem.192,623(1951). Folin-Wu assay used. .1. Biol. Chem. 41,307 (1920). V

be highly active.

. 9 cent concentrate of phosphatidylinositol was found to It is to be understood that the invention is not to be limited to the exact details of operation or compositions shown and described, as obvious modifications and equivalents will be aparent, to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims. t

We claim:

' 1. The process of preparing a soya phosphatide fraction which is well-suited for use as an emulsifier in an iutravenous fat product, which process comprises (1) contacting one part by weight of the monatomic, lower molecular weight aliphatic alcohol-dissolved soya phosphatides with about two parts by weight of an adsorbent selected from the group consisting of aluminum oxide, magnesium oxide and activated carbon, (2) removing the solids, and (3) recovering the desired soya phosphatide fraction from the solvent.

2. The process of preparing a soya phosphatide fraction whichis well-suited for use as an emulsifier in an intravenous fat product, which process comprises (1) contacting one part by weight of the soluble ethanoldissolvcd soya phosphatides with about two parts by weight ofaluminum oxide, (2) removing the solids, and (3) recovering the desired soya phosphatide fraction from the solvent.

3. The process of preparing a soya phosphatide frac- 'tion which is well-suited for use as an emulsifier in an intravenous fat product, which process comprises (1) contacting one part by weight of the soluble ethanol-dissolved soya phosphatides with about two'parts by weight of activated carbon, (2) removing the solids, and (3) recovering the desired soya phosphatide fraction from the solvent. r i

4. A stable soya phosphatide fraction (1) which can be prepared by .adsorbing'the undesirable reactive materials found in the monatomic, lower molecular weight aliphatic alcohol-dissolved soya phosphatides on about two parts by weight, based on said phosphatides, of an adsorbent selected from the group consisting of aluminum oxide, magnesium oxide and activated carbon, and

(2) which is a satisfactoryemulsifier for the oil used in a therapeutic fat product.

5. A stable soya phosphatide fraction (1) which can be prepared by adsorbing the undesirable reactive materials found the ethanol-dissolved soya phosphatides .on about two parts by weight, based on said phosphatides,

of aluminium oxides, (2) which is a satisfactory emulsifier for the oil used in a therapeutic fat product, and (3) which has the following approximate composition:

6. A stable soya phosphatide fraction (1) which can be prepared by adsorbing the undesirable reactive materials found in the ethanol-dissolved soya phosphatides on about two parts by weight, based on said phosphatides, of activated carbon, (2) which is a satisfactory emulsifier for the oil used in a therapeutic fat product, and (3) which has the following approximate composition:

Total nitrogen percent 1.45 Total phosphorus do 2.84 Choline .do 10.04 Inositol do 0.04 Ethanolamine do 0.4 Serine do 0.4 Iodine value (of total composition) 69.4 N:P molecular ratio 1.128 Reducing substance (as galactose) percent 28.3 Fatty'acids do 47.8 Iodine value (of fatty acids) 105.8

References Cited in the file of this patent UNITED STATES PATENTS 1,667,767 Bollmann May 1, 1928 1,776,720 Bollmann Sept. 23, 1930 2,154,432 Boericke Apr. 18, 1939 2,245,537 Thurman June 10, 1941 2,269,772 Kruse Jan. 13, 1942 2,728,706 Barsky Dec. 27, 1955 FOREIGN PATENTS 496,521 Canada Sept. 29, 1953 

1. THE PROCESS OF PREPARING A SOYA PHOSPHATIDE FRACTION WHICH IS WELL-SUITED FOR USE AS AN EMULSIFIER IN AN INTRAVENOUS FAT PRODUCT, WHICH PROCESS COMPRISES (1) CONTACTING ONE PART BY WEIGHT OF THE MONATOMIC, LOWER MOLECULAR WEIGHT ALIPHATIC ALCOHOL-DISSOLVED SOYA PHOSPHATIDES WITH ABOUT TWO PARTS BY WEIGHT OF AN ADSORBENT SELECTED FROM THE GROUP CONSISTING OF ALUMINUM OXIDE, MAGNESIUM OXIDE AND ACTIVATED CARBON, (2) REMOVING THE SOLIDS, AND (3) RECOVERING THE DESIRED SOYA PHOSPHATIDE FRACTION FROM THE SOLVENT. 